Paul F. Agris

Modification of messenger RNA by 2′-O-methylation regulates gene expression in vivo

Nature Communications · 2019-07-30 · 211 citations

Epitranscriptomic modifications of mRNA are important regulators of gene expression. While internal 2'-O-methylation (Nm) has been discovered on mRNA, questions remain about its origin and function in cells and organisms. Here, we show that internal Nm modification can be guided by small nucleolar RNAs (snoRNAs), and that these Nm sites can regulate mRNA and protein expression. Specifically, two box C/D snoRNAs (SNORDs) and the 2'-O-methyltransferase fibrillarin lead to Nm modification in the pr…

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

ChemMedChem · 2019-02-01 · 27 citations

Abstract The emergence of multidrug‐resistant bacteria necessitates the identification of unique targets of intervention and compounds that inhibit their function. Gram‐positive bacteria use a well‐conserved tRNA‐responsive transcriptional regulatory element in mRNAs, known as the T‐box, to regulate the transcription of multiple operons that control amino acid metabolism. T‐box regulatory elements are found only in the 5′‐untranslated region (UTR) of mRNAs of Gram‐positive bacteria, not Gram‐neg…

Physical Chemistry of a Single tRNA-Modified Nucleoside Regulates Decoding of the Synonymous Lysine Wobble Codon and Affects Type 2 Diabetes

The Journal of Physical Chemistry B · 2022-02-04 · 14 citations

The 2-methylthio-modification (ms2-) of N6-threonylcarbonyladenosine (t6A37) at position-37 (ms2t6A37) in tRNAUUULys3 provides the needed stability between the tRNA anticodon and the human insulin mRNA codon AAG during translation, as determined by molecular dynamics simulation. Single-nucleoside polymorphisms of the human gene for the enzyme, Cdkal1 that post-transcriptionally modifies t6A37 to ms2t6A37 in tRNAUUULys3, correlate with type 2 diabetes mellitus. Without the ms2-modification, tRNAU…

Small-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive Bacteria

Antimicrobial Agents and Chemotherapy · 2020-10-19 · 12 citations

(MRSA), and increased efficacy in nutrient-limiting conditions. The analogs have reduced cytotoxicity against eukaryotic cells compared to PKZ18. The PKZ18 analogs acted synergistically with aminoglycosides to significantly enhance the efficacy of the analogs and aminoglycosides, further increasing their therapeutic windows. RNA sequencing showed that the analog PKZ18-22 affects expression of 8 of 12 T-box controlled genes in a statistically significant manner, but not other 5'-UTR regulated gen…

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

Antibiotics · 2021-01-04 · 11 citations

Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would control multiple genes, and can be inhibited by a single compound. We previously demonstrated success against Staphylococcus aureus biofilms by targeting the tRNA-dependent regulated T-box…